P361: EARLY MEASURABLE RESIDUAL DISEASE ANALYSIS IS ONLY PREDICTIVE OF SURVIVAL OUTCOMES AFTER TWO CYCLES OF TREATMENT IN ADULTS WITH B-LYMPHOBLASTIC LEUKEMIA RECEIVING HYPER-CVAD INDUCTION.
Authors: R. Nedumannil, D. Ritchie, A. Bajel, A. P. Ng, S. J. Harrison, D. Westerman
Journal: HemaSphere (2022)

Background: Measurable residual disease (MRD) monitoring using multi-parametric flow cytometry (MFC) has a well-established role in B-lymphoblastic leukemia (B-ALL). However, the optimal time-point (TP) for early MRD testing and the associated prognostic impact remain undefined in adult B-ALL patients receiving Hyper-CVAD induction chemotherapy, a dose-intensive regimen comprising alternating A cycles (hyperfractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone) and B cycles (methotrexate and cytarabine). Aims: To evaluate the utility of MRD analysis by MFC after one cycle (TP1) in comparison to that after two cycles (TP2) of induction treatment in adult B-ALL patients receiving frontline Hyper-CVAD chemotherapy. Methods: A retrospective chart review was performed of consecutive patients older than 18 years with newly diagnosed B-ALL who received frontline Hyper-CVAD induction chemotherapy at two Australian tertiary referral centres from 2010-2020. Patient inclusion required data regarding remission and MRD statuses after each 21-day cycle of induction treatment (defined as two [A and B] cycles of Hyper-CVAD chemotherapy). Two flow cytometry panels (a two tube 8-color panel and a single tube 10-color panel) were used; samples were analyzed using Kaluza Analysis Software (Beckman Coulter) on FACSCanto II (BD Biosciences) and Navios EX (Beckman Coulter) cytometers, respectively. The sensitivity of these assays was 0.001%-0.01%. Clinicopathological and survival data [pertaining to overall survival (OS) and event-free survival (EFS)] were collected from review of patient records. Results: 49 of 76 (64%) adult B-ALL patients received frontline Hyper-CVAD chemotherapy and had available MFC MRD assessments at each of the two TPs. 19 patients (39%) had Philadelphia chromosome-positive (Ph+) disease and received concomitant tyrosine kinase inhibitor (TKI). Median times to TP1 and TP2 relative to start of treatment were 21 and 45 days, respectively. At TP1, 40 patients (82%) achieved complete remission (CR), amongst whom 12 (30%) were MRD negative. At TP2, the majority of patients (48, 98%) achieved CR, of whom 23 (48%) were MRD negative. Among those who achieved CR after Hyper-CVAD induction, 25 (52%) received Hyper-CVAD consolidation chemotherapy ± TKI while 24 (50%) proceeded to alloSCT in first CR. After cycle 1A, patients with residual morphological disease compared to those who attained CR had a median OS of 10 months and 44 months, respectively (HR, 6.15; 95% CI, 1.36-27.94; P = 0.019), while the median EFS was 58 months and not reached, respectively (HR, 1.31; 95% CI, 0.33-5.17; P = 0.423). MRD negativity at TP1 was not associated with a significant improvement in either OS (P = 0.426) or EFS (P = 0.335) when compared to patients with MRD positivity. In contrast, MRD negativity at TP2 was associated with significantly higher OS (P = 0·005) and EFS (P = 0.047) over patients with MRD positivity. Multivariate analysis demonstrated that KMT2A-rearrangement and MRD positivity at TP2 were the only factors (including Ph+ status) that correlated with worse EFS and OS. Summary/Conclusion: In the absence of residual morphologic disease, MRD analysis after one cycle of Hyper-CVAD induction chemotherapy does not correlate with survival outcomes when compared to MRD testing after two cycles of Hyper-CVAD in adult B-ALL patients. Although validation with larger studies is required, initial MRD testing after two cycles of Hyper-CVAD induction (i.e. after day 42) promotes appropriate resource utilization and ensures no loss in the prognostic power of early MRD monitoring in adult B-ALL.